Five-year follow-up update of defined-composition CD19 CAR T-cell therapy for relapsed/refractory CLL.
Authors: Emily C. Liang, Alexandre V. Hirayama, Erik Lesley Kimble, Andrew Jay Portuguese, Aya Albittar, Aude Chapuis, Mazyar Shadman, Brian G. Till, Ryan Daniel Cassaday, Filippo Milano, Cameron John Turtle, David G. Maloney, Jordan Gauthier
Journal: Journal of Clinical Oncology (2023)

7511 Background: We have described high response rates in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) treated with CD19-targeted CAR T cells. We now report comprehensive analyses of factors associated with duration of response (DOR) with a 68-month median follow-up. Methods: We included 49 pts with R/R CLL and/or Richter’s transformation (n = 10) treated on a phase I/II clinical trial of defined-composition CD19 CAR T-cell therapy (1:1 ratio of CD8+:CD4+). Response rates were investigator-assessed by 2018 iwCLL criteria. Measurable residual disease (MRD) in bone marrow (BM) was evaluated by multiparameter flow cytometry (MFC) and IGH next-generation sequencing (NGS; clonoSEQ assay). CAR T-cell enumeration was assessed by MFC. Serum cytokine concentrations (20 analytes) were measured by Luminex assay. Univariate associations between duration of response (DOR) and patient, disease, CAR T-cell manufacturing, and treatment-related variables were estimated using Cox regression (50+ variables). Association between CAR T-cell in vivo persistence and DOR was modeled with a time-dependent Cox model including blood CAR transgene levels (copies/µg genomic DNA). Results: Median age was 61 years (IQR, 55-67). Forty-six pts (94%) had complex karyotype and/or 17p deletion; 46 (94%) received cyclophosphamide/fludarabine lymphodepletion. In the response-evaluable cohort (n = 47), median follow-up was 68.3 months (IQR, 54.3-81.6). Overall and complete response rates at day+28 were 70% and 17%, respectively, and the median DOR was 22.2 months (95% CI, 10.7-not reached [NR]). MRD-negativity at day+28 by MFC occurred in 33/47 (70%). In pts with MRD-negativity by MFC and available data, MRD negativity by NGS was seen in 18/29 (62%). In NGS MRD-negative responders, the median DOR was 56.8 months (95% CI, 39.5-NR). In all evaluable patients, the 5-year OS and PFS were 35.5% (95% CI, 24.0%-52.5%) and 21.5% (95% CI, 12.0%-38.5%), respectively. In univariate Cox regression, day+28 MRD-negativity by MFC (HR = 0.03, 95% CI, 0.01-0.18, p &lt; 0.001), day+28 MRD-negativity by NGS (HR = 0.21, 95% CI, 0.07-0.61, p = 0.004), peak CD8+ CAR T-cell expansion (HR = 0.49, 95% CI, 0.24-1.00, p = 0.05), CAR T-cell persistence (HR = 0.71, 95% CI, 0.54-0.91, p = 0.01), and lower peak MIP-1β (HR = 3.12, 95% CI, 1.13-8.65, p = 0.03) were associated with longer DOR. Peak MIP-1β remained associated with DOR (HR = 3.83, 95% CI, 1.35-10.9, p = 0.012) in a multivariable model including pre-LD CLL cells in BM, tumor cross-sectional area, peak CD8+ CAR T-cell expansion, and day+28 MRD by MFC. Conclusions: CD19 CAR T-cell therapy achieved durable remissions in R/R CLL pts. Day+28 MRD, CAR T-cell peak expansion, and CAR T-cell persistence were strongly associated with DOR. Lower peak serum levels of MIP-1β, a cytokine known to be produced by CLL cells upon BCR activation, was strongly and independently associated with DOR. Clinical trial information: NCT01865617 .